The present invention is concerned with novel benzofused lactams which are effective inhibitors of angiotensin I converting enzyme and effective antagonists of cholecystokinin. These novel compounds are, consequently, combined with pharmaceutically acceptable carriers to form pharmaceutical compositions of the present invention and are used in a method of treating hypertension, gastrointestinal disorders, central nervous system disorders, or regulating appetite in humans.
Angiotensin II, a powerful vasoconstrictor hormonal peptide, is formed from the inactive angiotensin I by the action of angiotensin converting enzyme (ACE). Recently, potent inhibitors of ACE have been reported which are capable of lowering the blood pressure in hypertensive patients. The novel benzofused lactams of the present invention are also potent inhibitors of ACE.
Cholecystokinin (CCK) is a neuropeptide composed of thirty-three aminoacids. See: Mutt and Jorpes, Biochem. J. 125 678 (1971). The carboxyl terminal octapeptide (CCK-8) also occurs naturally and is fully active. CCK exists in both gastrointestinal tissue and the central nervous system. V. Mutt, Gastrointestinal Hormones, G. B. J. Glass, Ed., Raven Press, N.Y., (1980) p. 169. CCK is believed to play an important role in appetite regulation and CCK may be a physiological satiety hormone. G. P. Smith, Eating and Its Disorders, A. J. Stunkard and E. Stellar, Eds, Raven Press, New York, 1984, p. 67.
Among additional effects of CCK are stimulation of colonic motility, stimulation of gall bladder contraction, stimulation of pancreatic enzyme secretion, and inhibition of gastric emptying. CCK reportedly co-exists with dopamine in certain mid-brain neurons and thus may also play a role in the functioning of dopaminergic systems in the brain as well as serving as a neurotransmitter in its own right. See: A. J. Prange et al., "Peptides in the Central Nervous System", Ann. Repts. Med. Chem. 17 31, 33 (1982) and references cited therein; J. A. Williams, Biomed. Res. 3 107 (1982); and J. E. Morley, Life Sci. 30, 479 (1982).
CCK antagonists are useful in the treatment and prevention of CCK-related disorders of the gastrointestinal, central nervous and appetite regulatory systems of animals, especially humans. Three distinct chemical classes of CCK receptor antagonists have been reported. One class comprises derivatives of cyclic nucleotides; detailed structure-function studies have demonstrated that of the various members of this class, dibutyryl cyclic GMP is the most potent. See; N. Barlos et al., Am. J. Physiol., 242, G161 (1982) and P. Robberecht et al., Mol. Pharmacol., 17, 268 (1980). The second class comprises peptide antagonists which are C-terminal fragments and analogs of CCK. Recent structure-function studies have shown that both shorter C-terminal fragments of CCK (Boc-Met-Asp-Phe-NH.sub.2, Met-Asp-Phe-NH.sub.2) as well as longer CCK fragments (Cbz-Tyr(SO.sub.3 H)-Met-Gly-Trp-Met-Asp-NH.sub.2) can function as CCK antagonists. See: R. T. Jensen et al., Biochim. Biophys. Acta., 757, 250 (1983) and M. Spanarkel et al., J. Biol. Chem., 258, 6746 (1983). The third class of CCK receptor antagonists comprises the amino acid derivatives; proglumide, a derivative of glutaramic acid, and the N-acyl tryptophans including para-chlorobenzoyl-L-tryptophan (benzotript). See W. F. Hahne et al., Proc. Natl. Acad. Sci. U.S.A., 78, 6304 (1981) and R. T. Jensen et al., Biochem. Biophys. Acta., 761, 269 (1983). All of these compounds are relatively weak antagonists of CCK (IC.sub.50 : 10.sup.-4 -10.sup.-6 M).